Predicted difficulties in achieving vaccine protection against HIV and SIV have more or less been borne out by vaccine trials in animal models. Our laboratory has demonstrated impressive protective effects of live- attenuated, deletion mutations of SIV as preventive vaccines. The live- attenuated approach has significantly out-performed other vaccine approaches in rhesus monkey models. Although we do not have definitive knowledge on the immunological basis for the protection, continued antigen expression resulting from viral persistence may be a key factor. A variety of studies have suggested that immunological memory is simply not sufficient to protect against pathogenic, difficult-to-neutralize strains of SIV that would be representative of primary isolates of HIV1. We will investigate whether persistent, vectored expression of SIV antigens resulting from infection by recombinant herpesvirus can match the live- attenuated approach for protective efficacy. The alpha herpesvirus, herpes simplex virus (HSV), and the gamma herpesvirus, rhesus monkey rhadinovirus (RRV), will be used in vaccine/challenge experiments in monkeys. viral genes that contribute to pathogenic potential will be removed from these herpesviruses and replaced by cassettes for expression of SIV genes. Viruses expressing SIV env, gag-pol and gal-pol + env will be compared for their capacity to protect against mucosal challenge by wild-type, disease-inducing strains of SIV. The properties of herpesviruses that utilize a constitutive SV40 promoter versus endogenous herpesviral promoters for vectored expression will be compared since a regulated herpesvirus promoter may be needed for high level persistence and maximal immune responses. The ability of replication competent versus replication defective strains of recombinant herpesviruses to elicit high-titer immune responses and protection will also be compared. The proposed studies are expected to define conditions that are needed to achieve solid vaccine protection against SIV by recombinant herpesviruses.